Breast cancer remains one of the leading causes of cancer-related mortality worldwide. Fulvestrant is an advanced therapeutic agent characterized by a unique chemical structure and mechanism of action targeting the estrogen receptor (ER). In this study, estradiol was used as a reference ligand to establish a direct comparison between the endogenous hormone involved in estrogen-dependent signaling in ER-positive breast cancer and the antagonist drug designed to inhibit receptor activation. The investigation was conducted using conformational search, quantum-chemical calculations, molecular docking, and molecular dynamics simulations to elucidate differences in the molecular behavior of estradiol and fulvestrant, with particular emphasis on the ligand-binding domain and the AF-2 region of the estrogen receptor. Docking results revealed that fulvestrant exhibits a docking score of −9.34 kcal/mol using the Vina scoring function, whereas estradiol showed a more favorable score of −11.34 kcal/mol. Owing to the conformational flexibility of fulvestrant, a conformational search was performed using CREST prior to the DFT analysis, and the lowest-energy CREST conformer remained the lowest-energy structure among the selected conformers after DFT reoptimization. The reactivity properties of the ligands were evaluated within the framework of density functional theory (DFT) employing the M06-2X functional and the 6-311+G(d,p) basis set. Furthermore, charge-transfer values (ΔN) calculated between the ligands and amino acid models of the receptor binding site were used to qualitatively characterize relative electron-density transfer tendencies. Molecular docking predictions were complemented by two independent molecular dynamics simulations for each ligand performed using the GROMACS 2026.1 software package, allowing the evaluation of receptor–ligand stability under solvated conditions.
Three 1-pyrrolidinyl 8-halo and one 1-pyrrolidinyl 8-cyano-substituted naphthalenes are prepared. The rate of the rotation of the pyrrolidinyl group is determined through variable temperature proton NMR using line-shape analysis and EXSY. The potential energy of the rotation is modeled through DFT calculations using the aug-cc-pVDZ-PP basis set. The activation energies are compared with the experimental values. The strain components of the transition states are obtained from molecular mechanics analysis using MM3. The activation energies follow the steric footprint of the halogen/nitrile: I > Br > Cl > CN. Rotation requires significant twisting and splaying of the naphthalene framework and inversion of the pyrrolidine nitrogen atom. The twisted naphthalene snaps backwards as the barrier is traversed, giving the opposite helicity.
The incorporation of ferrocene into established pharmacophores represents a promising strategy for combining targeted activity with the properties of the organometallic scaffold. Building on our previous work on ferrocene-modified tyrosine kinase inhibitors (TKIs), this study presents the synthesis, biological evaluation and molecular docking analysis of four novel 1,1′-desymmetrized ferrocenyl derivatives of imatinib and nilotinib, designed to investigate how subtle structural modifications of the ferrocenyl moiety influence their cytotoxic activity and predicted interactions with the ABL1 kinase domain. The imatinib-derived compounds 5 and 6 contain amino and acetamido substituents, respectively, whereas the nilotinib-derived compounds 16 and 17 incorporate acetyl and benzoyl functionalities. Their cytotoxic activity was evaluated against four BCR::ABL1-positive leukemia cell lines with distinct molecular characteristics (BV-173, K-562, AR-230, and LAMA-84), with non-malignant CCL-1 fibroblasts included for assessment of selectivity and imatinib used as a reference drug. All four derivatives exhibited cytotoxic activity, with pronounced structure- and cell line-dependent differences. Compound 5 showed the most favorable activity profile, with pronounced cytotoxicity against AR-230 cells and activity comparable to or greater than imatinib in BV-173 and K-562 cells. In contrast, compound 17 was the most active derivative in LAMA-84 cells and exhibited the highest selectivity among all analogues in the series across the entire leukemia panel. Molecular docking indicated that ferrocenyl incorporation altered the binding orientation within the ABL1 kinase domain, while compound 5 showed the smallest positional deviation, consistent with its favorable cytotoxic profile. The results demonstrate that additional functionalization of the ferrocenyl moiety produces cell-line-dependent changes in cytotoxic activity without consistently improving potency or selectivity compared with previously reported monosubstituted analogues. Nevertheless, the successful synthesis of 1,1′-desymmetrized ferrocene conjugates provides new opportunities for structural diversification and further optimization of this class of compounds.
Pladienolide B (1), a macrocyclic polyketide isolated from Streptomyces platensis Mer-11107, displays potent antiproliferative and antitumor activities through its interaction with the SF3b subunit of the spliceosome. Herein, we report a divergent, stereoselective synthetic route to access both the C1–C8 and C9–C13 fragments of the core moiety of Pladienolide B (1) starting from a common, inexpensive chiral-pool precursor, L-Malic acid. Key stereocenters and structural motifs were established using Sharpless asymmetric epoxidation, regioselective nucleophilic epoxide opening, Mannich reaction for exo-methylene introduction, and a tandem iodination–zinc elimination cascade. This unified precursor approach offers a streamlined tactical route toward the core macrolide framework.
A series of five novel 3-methyl-1-phenyl-4-(4-thioaroyl)-pyrazol-5-ones is obtained in excellent yields by thionation of the corresponding O-analogues with Lawesson’s reagent. The products are characterized in solution and solid phase. It is found that only mono-thionation occurs and that the products exist in enol-thione forms. Atypical side products are isolated and characterized. The preferred solid state forms are analyzed and compared with those of the corresponding O-analogues.
